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Study of unprecedented size reveals how sex ‘blindspot’ could misdirect medical research

By James Sudlow, 26.6.17

Scientists at the International Mouse Phenotyping Consortium suggest that sex should be a mandatory consideration in the design of animal research studies.

It is well known that the prevalence, course and severity for many diseases including cardiovascular diseases, autoimmune diseases and asthma is heavily influenced by whether we are male or female, yet up until now the role of sex in animal research has not been fully explored. In fact, for consistency most animal research is only done on males and in two thirds of the research that does use two sexes, the results are not analysed by sex.

Many papers and funding bodies have raised the need to consider sex as an important variable, with the National Institute of Health going as far to make it a mandatory requirement in a recent policy change. This was however met with some resistance with many arguing that scientists should be trusted to know when sex plays a role, and with concerns being raised over the cost associated with duplicating experiments in both sexes.

To address this problem, researchers at the IMPC have performed one of the largest studies to date on the effect of sex on biomedical research, analysing up to 234 physical characteristics of more than 50,000 mice.

Burrowing into the data, the team found that in the standard group of mice – the control mice – their sex had an impact on 56.6 per cent of quantitative traits, such as body weight, and on 9.9 per cent of qualitative traits, such as the shape of the whiskers. In mice that had a gene switched off – the mutant mice – their sex modified the effect of the mutation in 13.3 per cent of qualitative traits and up to 17.7 per cent of quantitative traits. Importantly, in many of these cases the sex of the animal was not expected to have an effect, refuting the idea that researchers could simply address sex when it was predicted to be an issue in advance of the study.

This research supports the idea that regardless of research field or biological system, sex should be an important consideration in the design and analysis of animal studies. Dr Natasha Karp, lead author who carried out the research at the Wellcome Trust Sanger Institute, and now works in the IMED Biotech Unit at AstraZeneca, said: “This was a scientific blindspot that we really thought needed exploration. A person’s sex has a significant impact on the course and severity of many common diseases, and the consequential side effects of treatments – which are being missed.”

This study presents implications for the design of future animal studies and clinical trials. It has been more than twenty years since it became a requirement that women were included within clinical trials in the US.1 Whilst more women are taking part in clinical trials, increasing from 9 per cent in 1970 to 41 per cent 20062, women are still under-represented.

The bias is even stronger in the earlier stages of biomedical research. A review of international animal research between 2011 and 2012 found that 22 per cent of studies did not state the sex of the animals, and of those that did, 80 per cent of studies used solely males and only 3 per cent included both males and females.3

Professor Steve Brown, an author of the study and Chair of the International Mouse Phenotyping Consortium Steering Committee, said: “It is likely that important scientific information is missed by not investigating more thoroughly how males and females differ in biomedical research. Rather than extrapolate the results to account for the opposite sex, these results suggest designing experiments to include both sexes in the study of disease. This study is a major step to highlighting the impact of sex differences in research and will help in accounting for those differences in the future of biomedicine.”